Zscan4c activates endogenous retrovirus MERVL and cleavage embryo genes
Zscan4c activates endogenous retrovirus MERVL and cleavage embryo genes
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Zscan4c 激活内源性逆转录病毒 MERVL 并裂解胚胎基因
DOI：
10.1093/nar/gkz594
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发表时间：
2019
影响因子：
14.9
通讯作者：
Lu Xinyi
中科院分区：
文献类型：
--
作者：
Zhang Weiyu;Chen Fuquan;Chen Ruiqing;Xie Dan;Yang Jiao;Zhao Xin;Guo Renpeng;Zhang Yongwang;Shen Yang;Goke Jonathan;Liu Lin;Lu Xinyi
内源性逆转录病毒（ERV）占小鼠基因组的约10%。它们通常在分化的体细胞中沉默，但在不同的胚胎发育阶段差异表达。少数小鼠胚胎干细胞（ESC），如2-细胞分裂胚胎，高度表达ERV MERVL。然而，ERVs的作用及其在这些细胞中的激活机制仍然知之甚少。在这项研究中，我们研究了阶段特异性表达的ERVs的调节和功能，特别关注全能性标志物MT 2/MERVL。我们表明，转录因子Zscan 4c的功能作为MT 2/MERVL和2-细胞/4-细胞胚胎基因的激活剂。Zscan 4c的锌指结构域在这一过程中起着重要作用。此外，Zscan 4c与MT 2相互作用并通过促进MT 2的增强子活性来调节MT 2附近的2-细胞/4-细胞基因。此外，MT 2活化伴随着MT 2上增强的H3 K4 me 1、H3 K27 ac和H3 K14 ac沉积。Zscan 4c还通过SCAN结构域与GBAF染色质重塑复合物相互作用，以进一步激活MT 2增强子活性。总之，我们描绘了一个以前未被认识到的调控轴，Zscan 4c相互作用，并激活MT 2/MERVL基因座及其附近的基因，通过表观遗传调控。
Endogenous retroviruses (ERVs) contribute to ∼10 percent of the mouse genome. They are often silenced in differentiated somatic cells but differentially expressed at various embryonic developmental stages. A minority of mouse embryonic stem cells (ESCs), like 2-cell cleavage embryos, highly express ERV MERVL. However, the role of ERVs and mechanism of their activation in these cells are still poorly understood. In this study, we investigated the regulation and function of the stage-specific expressed ERVs, with a particular focus on the totipotency marker MT2/MERVL. We show that the transcription factor Zscan4c functions as an activator of MT2/MERVL and 2-cell/4-cell embryo genes. Zinc finger domains of Zscan4c play an important role in this process. In addition, Zscan4c interacts with MT2 and regulates MT2-nearby 2-cell/4-cell genes through promoting enhancer activity of MT2. Furthermore, MT2 activation is accompanied by enhanced H3K4me1, H3K27ac, and H3K14ac deposition on MT2. Zscan4c also interacts with GBAF chromatin remodelling complex through SCAN domain to further activate MT2 enhancer activity. Taken together, we delineate a previously unrecognized regulatory axis that Zscan4c interacts with and activates MT2/MERVL loci and their nearby genes through epigenetic regulation.